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A multivalent signal-transducing model for the DNMT1-mediated maintenance DNA methylation

UID: 10651

Author(s): Wang, Gang G., Grimm, Sara A.

Description
Summary from the GEO: "Heterochromatin-specific histone modifications frequently coexist with mammalian DNA methylation to orchestrate a repressive chromatin state. However, it remains elusive how these epigenetic modifications crosstalk. Here, we report that the first bromoadjacent homology (BAH1) domain and the replication foci targeting sequence (RFTS) of maintenance DNA methyltransferase DNMT1 function as readers for H4K20me3 and H3K9me3, respectively. Engagements of H4K20me3 by BAH1 and H3K9me3 by RFTS ensure localization of DNMT1 to heterochromatin in cells, and cooperate with the RFTS-ubiquitination readout to allosterically stimulate DNMT1 s methylation activity at both global and focal levels. Strikingly, there is intramolecular crosstalk between the RFTS and BAH1 domains, which profoundly impacts the maintenance of DNA methylation and genomic resistance to radiation damage. Together, our study reveals an all-in-one model for DNMT1 in which repressive histone modifications directly influence the cellular landscape of DNA methylation and genomic stability, a process implicative of the DNMT1-related pathogenesis."

Overall design from the GEO:"To examine patterns of maintenance DNA methylation deposited by DNMT1 in cells, we stably transduced either WT or mutant DNMT1 into mouse ES cells with knockout (KO) of DNMT1 (1KO), followed by genome-wide methylation in cells by enhanced reduced representation bisulfite sequencing (eRRBS). eRRBS was carried out side-by-side in three biological replicates of the 1KO rescued lines to generate datasets for across-sample comparisons."
Subject of Study
Mus musculus
Subject(s)
DNA (Cytosine-5-)-Methyltransferase 1
DNA Methylation
Heterochromatin
Histone Code
Histones
Access via GEO

Plain Text and BigWig files of methylation profiling by high throughput sequencing
Accession #: GSE145698

Access via SRA

BiSulfate Sequencing for 18 Samples
Accession #: SRP250290

Access via BioProject

Additional information about overall initiative.
Accession #: PRJNA607973

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus, SRA, and BioProject databases provide open access to these files.
Associated Publications
Ren W, Fan H, Grimm S, et al. Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation. Proceedings of the National Academy of Sciences of the United States of America. 2020; 117(31):18439-18447.
Ren W, Fan H, Grimm S, et al. DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation. Nature Communications. 2021; 12:2490.
Data Type
Genomic
Equipment Used
Illumina HiSeq 4000

High throughput gene sequencing system

Software Used
SRA Toolkit

The NCBI SRA Toolkit enables reading ("dumping") of sequencing files from the SRA database and writing ("loading") files into the .sra format.

Dataset Format(s)
Plain Text, TAR, BIGWIG
Data Tool(s)
Bisulfite-Seq
Dataset Size
461.6 Mb (TAR of BIGWIG), 338.3 Mb (TXT), 259.3 Gb (SRA)
Data Catalog Record Updated
2023-12-07